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首页> 外文期刊>The Open Medicinal Chemistry Journal >Identification of G-Quadruplex Inducers Usinga Simple, Inexpensiveand Rapid High Throughput Assay, and TheirInhibition of Human Telomerase
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Identification of G-Quadruplex Inducers Usinga Simple, Inexpensiveand Rapid High Throughput Assay, and TheirInhibition of Human Telomerase

机译：使用简单，廉价和快速的高通量分析鉴定G四联体诱导剂及其对人类端粒酶的抑制作用

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摘要

Telomeres are protein and DNA complexes located atchromosome ends. Telomeric DNA is composed of a double stranded region of repetitive DNA followed by single-stranded 3' extension of aG-rich sequence. Single-stranded G-rich sequencescan fold into G-quadruplex structures,and molecules that stabilize G-quadruplexes are known to inhibit the enzyme telomerase and disrupt telomere maintenance. Because telomere maintenance is required for proliferation of cancer cells, G-quadruplex stabilizers have become attractive prospects for anticancer drug discovery.However, telomere-targeting G-quadruplex ligands have yet to enter the clinic owing in part to poor pharmacokinetics and target selectivity. Increasing the pharmacophore diversity of G-quadruplex and specifically telomeric-DNA targeting agents should assist in overcoming these shortcomings. In this work, we report the identification and validation ofligands that bind telomeric DNA and induce G-quadruplex formationusing the NCI Diversity Set I, providing validation of anextremely simple, rapid and high-throughput screen using FRET technology. Hits from the screen were validated by examining telomerase inhibition and G-quadruplex inductionusing CD spectroscopy and DNA polymerase stop assays. We show that two known DNA binding molecules, ellipticine derivativeNSC 176327 (apyridocarbazole) and NSC 305831 (an antiparasitic hetero-cyclediamidine referred to as furamidine and DB75),are selective induceG-quadruplex formation in the human telomeric sequence and bind telomeric DNA quadruplexes in the absence of stabilizing monovalent cations with molar ratios(molecule: DNA)of 4:1and 1.5:1, respectively.
机译：端粒是位于染色体末端的蛋白质和DNA复合物。端粒DNA由重复DNA的双链区和富aG序列的单链3'延伸组成。单链富含G的序列可折叠成G-四链体结构，稳定G-四链体的分子可抑制端粒酶并破坏端粒的维持。由于端粒维持是癌细胞增殖所必需的，因此G-四链体稳定剂已成为发现抗癌药物的诱人前景。然而，靶向端粒的G-四链体配体尚未进入临床，部分原因是药物动力学和靶标选择性差。增加G-四链体，特别是端粒-DNA靶向剂的药效基团多样性应有助于克服这些缺点。在这项工作中，我们报告了使用NCI多样性I鉴定结合端粒DNA并诱导G-四链体形成的配体的鉴定和验证，从而使用FRET技术验证了极其简单，快速和高通量的筛选。通过使用CD光谱和DNA聚合酶终止检测检查端粒酶抑制和G-四链体诱导来验证筛选结果。我们显示两个已知的DNA结合分子，玫瑰树碱衍生物NSC 176327（apyridocarbazole）和NSC 305831（一种抗寄生虫杂环二m称为呋喃idine和DB75），在人端粒序列中选择性诱导G-四链体形成并在端粒中结合端粒DNA四链体。摩尔比（分子：DNA）分别为4：1和1.5：1的稳定单价阳离子。

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